Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis

Microbe-macrophage interactions play a central role in the pathogenesis of many infections. The ability of some bacterial pathogens to induce macrophage apoptosis has been suggested to contribute to their ability to elude innate immune responses and successfully colonize the host. Here, we provide evidence that activation of liver X receptors (LXRs) and retinoid X receptors (RXRs) inhibits apoptotic responses of macrophages to macrophage colony-stimulating factor (M-CSF) withdrawal and several inducers of apoptosis. In addition, combined activation of LXR and RXR protected macrophages from apoptosis caused by infection with Bacillus anthracis, Escherichia coli, and Salmonella typhimurium. Expression-profiling studies demonstrated that LXR and RXR agonists induced the expression of antiapoptotic regulators, including AIM/CT2, Bcl-X(L), and Birc1a. Conversely, LXR and RXR agonists inhibited expression of proapoptotic regulators and effectors, including caspases 1, 4/11, 7, and 12; Fas ligand; and Dnase1l3. The combination of LXR and RXR agonists was more effective than either agonist alone at inhibiting apoptosis in response to various inducers of apoptosis, and it acted synergistically to induce expression of AIM/CT2. Inhibition of AIM/CT2 expression in response to LXR/RXR agonists partially reversed their antiapoptotic effects. These findings reveal unexpected roles of LXRs and RXRs in the control of macrophage survival and raise the possibility that LXR/RXR agonists may be exploited to enhance innate immunity to bacterial pathogens that induce apoptotic programs as a strategy for evading host responses.     

Post-translational polymodification of b1-tubulin regulates motor protein localization in platelet production and function

In specialized cells, the expression of specific tubulin isoforms and their subsequent post-translational modifications drive and coordinate unique morphologies and behaviors. The mechanisms by which b1-tubulin, the platelet and megakaryocyte (MK) lineage restricted tubulin isoform, drives platelet production and function remains poorly understood. We investigated the roles of two key post-translational tubulin polymodifications (polyglutamylation and polyglycylation) on these processes using a cohort of thrombocytopenic patients, human induced pluripotent stem cell derived MK, and healthy human donor platelets. We find distinct patterns of polymodification in MK and platelets, mediated by the antagonistic activities of the cell specific expression of tubulin tyrosine ligase like enzymes and cytosolic carboxypeptidase enzymes. The resulting microtubule patterning spatially regulates motor proteins to drive proplatelet formation in megakaryocytes, and the cytoskeletal reorganization required for thrombus formation. This work is the first to show a reversible system of polymodification by which different cell specific functions are achieved.     

Gross energy metabolism in mice under late onset, short term caloric restriction

Late onset, short-term moderate caloric restriction (CR) may have beneficial health effects. A 26% CR regime induced at 14 months of age for 70 days in male C57Bl/6 (ICRFa) mice resulted in a reduction in body mass of 17%. A decrease in daily energy expenditure was associated with decreased body mass in CR mice. There was no difference in total levels of physical activity between the CR and ad libitum (AL) groups; however, activity patterns were different. We developed a Bayesian model to dissect the impact of food anticipation activity (FAA) and feeding on physical activity. FAA was stronger in CR mice and remaining basal activity was higher in AL mice, but CR mice displayed larger diurnal variations as well as a phase shift in their diurnal activity. CR mice displayed lower body temperature, especially late during the dark phase. This was due to lower basal (activity-independent) temperature at all times of the day, coupled to a phase shift in the diurnal rhythm. The correlation between body temperature and physical activity was independent of feeding regimen and light/dark cycles. Reduction of body mass and basal temperature were major compensatory mechanisms to reduced food availability during late-onset, short-term CR.     

Concise, stereoselective route to the four diastereoisomers of 4-methylproline

The full stereochemical characterization of 4-methylproline, a rare amino acid found in a number of peptidic secondary metabolites, has often been hindered by long reaction sequences or low stereoselectivity in the synthesis leading to reference samples. The preparation of the four diastereoisomers of 4-methylproline by a concise and stereoselective route is presented and features a six-step route with late-stage stereodivergence, good stereoselectivity for both cis- and trans-series (75% and 88% de, respectively), and good overall yields (cumulative yields of 30-40%). Additional data on the Marfey's derivatives of the stereoisomers are also presented.     

An unusual and life-threatening cause of epigastric pain presenting to the general surgical team: a case report

As general surgeons, we are regularly referred patients with epigastric pain. There are a huge number of common pathologies which cause this complaint, most of which are gastrointestinal in origin. Although the old adage goes ’common things are common’, we must always keep our minds open to the possibility of the uncommon and not miss warning signs which are present in the history or examination. We present the case of a 59-year-old woman with a ruptured sinus of Valsalva aneurysm presenting to the accident and emergency department as epigastric pain.     

Drug use functions predict cocaine-related problems in young people

Over the last decade, concern about young people and stimulant drugs has primarily focused on the use of amphetamines and ecstasy. In the United Kingdom, this concern has recently expanded to include the use of cocaine hydrochloride (powder cocaine). This study examined patterns of illicit substance use, with a particular focus on cocaine consumption, among a sample of 364 young drug users aged between 16 and 22 years. The sample was recruited using snowballing methods and respondents were interviewed in informal settings by peer interviewers. Over half the sample reported lifetime use of powder cocaine and just over 40% of these had used crack cocaine. A seven item scale was used to measure cocaine-related problems. The three most common problems endorsed by the cocaine users were impaired control, 'prioritizing spending money on cocaine over other things' and being pre-occupied with using. In a multiple regression analysis, 50% of the variance in cocaine-related problem scores was predicted by the perceived functions for cocaine use, the number of times of lifetime cocaine use and the total number of days of recent stimulant use. Use of cocaine to alleviate depressed state or negative mood was the most powerful predictor of cocaine problems. The inclusion of a functional appraisal component could be usefully incorporated in further research studies and in service assessment protocols for young people.     

Anti-oestrogens but not oestrogen deprivation promote cellular invasion in intercellular adhesion-deficient breast cancer cells

Introduction  

Anti-oestrogens have been the mainstay of therapy in patients with oestrogen-receptor (ER) positive breast cancer and have provided significant improvements in survival. However, their benefits are limited by tumour recurrence in a significant proportion of initially drug-responsive breast cancer patients because of acquired anti-oestrogen resistance. Relapse on such therapies clinically presents as local and/or regional recurrences, frequently with distant metastases, and the prognosis for these patients is poor. The selective ER modulator, tamoxifen, classically exerts gene inhibitory effects during the drug-responsive phase in ER-positive breast cancer cells. Paradoxically, this drug is also able to induce the expression of genes, which in the appropriate cell context may contribute to an adverse cell phenotype. Here we have investigated the effects of tamoxifen and fulvestrant treatment on invasive signalling and compared this with the direct effects of oestrogen withdrawal to mimic the action of aromatase inhibitors.